02182nas a2200313   4500000000100000008004100001260001600042100001400058700001500072700002100087700001300108700001600121700001400137700001300151700001200164700001100176700001000187700001200197700001500209700001300224700001500237700001200252700001200264700001400276700001700290245016400307520138300471022001401854       2014                            d  c2014 Feb 191 aMattos KA1 aOliveira V1 aBerrêdo-Pinho M1 aAmaral J1 aAntunes LCM1 aMelo RC N1 aAcosta C1 aMoura D1 aOlmo R1 aHan J1 aRosa PS1 aAlmeida PE1 aFinlay B1 aBorchers C1 aSarno E1 aBozza P1 aAtella GC1 aPessolani MC00aMycobacterium leprae intracellular survival relies on cholesterol accumulation in infected macrophages: a potential target for new drugs for leprosy treatment.3 a<p>We recently showed that Mycobacterium leprae (ML) is able to induce lipid droplet formation in infected macrophages. We herein confirm that cholesterol (Cho) is one of the host lipid molecules that accumulate in ML-infected macrophages and investigate the effects of ML on cellular Cho metabolism responsible for its accumulation. The expression levels of LDL receptors (LDL-R, CD36, SRA-1, SR-B1, and LRP-1) and enzymes involved in Cho biosynthesis were investigated by qRT-PCR and/or Western blot and shown to be higher in lepromatous leprosy (LL) tissues when compared to borderline tuberculoid (BT) lesions. Moreover, higher levels of the active form of the sterol regulatory element-binding protein (SREBP) transcriptional factors, key regulators of the biosynthesis and uptake of cellular Cho, were found in LL skin biopsies. Functional in vitro assays confirmed the higher capacity of ML-infected macrophages to synthesize Cho and sequester exogenous LDL-Cho. Notably, Cho colocalized to ML-containing phagosomes, and Cho metabolism impairment, through either de novo synthesis inhibition by statins or depletion of exogenous Cho, decreased intracellular bacterial survival. These findings highlight the importance of metabolic integration between the host and bacteria to leprosy pathophysiology, opening new avenues for novel therapeutic strategies to leprosy.</p>
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